Hemostatic and thrombotic disorders are among the leading causes of morbidity and mortality in the United States. Platelet activation and the subsequent binding of macromolecular ligands to the integrin alphaIIbbeta3 are critical events in the pathogenesis of these disorders. The objective of this SCOR Program is to further understanding of the mechanism and consequences of platelet activation, both at the laboratory and clinical levels, with the ultimate goal of providing a rational basis for new and novel therapies. The SCOR Program is composed of five projects and one core unit. Project 1 examines the structural features of alphaIIbbeta3 involved in its activation by platelet agonists. The structure of its ligand binding sites and its cytoplasmic and transmembrane domains will be studied, as well the interaction of the cytoplasmic domains with the platelet cytoskeleton. The latter studies are based on hypothesis that the platelet cytoskeleton regulates alphaIIbbeta3 function. Project 2 examines the biochemistry and cell biology of the platelet protein pleckstrin, asking how pleckstrin regulates cytoskeletal organization, how it affects megakaryocyte development, and what are its physiological ligands. Project 3 examines the consequences of eicosinoid receptor activation. Questions to be addressed include the role of thromboxane receptor activation in atherogenesis and plaque progression, and whether thromboxane receptor activation in atherogenesis and plaque progression, and Project 4 is to define the molecular basis of heparin- associated thrombocytopenia (HIT). The antigenic sites on PF4/heparin responsible for HIT will be characterized, the pathogenicity of various HIT antibodies for thrombosis will be studied, and two murine HIT models will be used to identify factors that predispose to thrombosis. Project 6 is based on the observation that most platelet agonists active platelets via one or more G protein coupled receptors on the platelet surface. Questions asked include whether simultaneous activation of multiple G proteins is required for platelet activation, what are the consequences in vivo of sustained signaling through G proteins, and do RGS proteins limit the duration of G protein signaling to prevent inappropriate platelet activation? The five projects will be supported by an Administrative Core that provides for the administrative and secretarial requires of the SCOR Program.